Pharmaceutical composition

ABSTRACT

Pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with other antidiabetics differing from the enhancer in the mechanism of action, which shows a potent depressive effect on diabetic hyperglycemia and is useful for prophylaxis and treatment of diabetes.

FIELD OF THE INVENTION

[0001] The present invention relates to a pharmaceutical compositioncomprising an insulin sensitivity enhancer in combination with one ormore other antidiabetics differing from said enhancer in the mechanismof action.

BACKGROUND OF THE INVENTION

[0002] Recent years, the pathology of diabetes has become more and moreunderstood and, in parallel, drugs specific for the respectivepathologic states have been developed. Accordingly a variety of drugshaving new mechanisms of action have appeared one after another.

[0003] Insulin sensitivity enhancers are also known as insulinresistance deblockers because they have the action to normalize theimpaired insulin receptor function, and are gathering much attention inthese years.

[0004] Regarding such insulin sensitivity enhancers, a very usefulcompound such as pioglitazone has been developed [Fujita et al.,Diabetes, 32, 804-810, 1983, JP-A S55(1980)-22636 (EP-A 8203), JP-AS61(1986)-267580 (EP-A 193256)]. Pioglitazone restores the impairedinsulin receptor function to normalize the uneven distribution ofglucose transporters in cells, the cardinal enzyme systems associatedwith glycometabolism, such as glucokinase, and enzyme systems associatedwith lipidmetabolism, such as lipoprotein lipase. As the results,insulin resistance are deblocked to improve glucose tolerance, and lowerthe plasma concentrations of neutral lipids and free fatty acids. Sincethese actions of pioglitazone are comparatively gradual and the risk ofside effect in long-term administration is also low, this compound isuseful for obese patients who are presumed to be highlyinsulin-resistant.

[0005] Also, insulin sensitivity enhancers such as CS-045,thiazolidinedione derivatives and substituted thiazolidinedionederivatives are reported to be used in combination with insulin [JP-AH4(1992)-66579, JP-A H4(1992)-69383, JP-A H5(1993)-202042]. However, thepharmaceutical composition having a specific combination of the presentinvention is unknown.

[0006] Diabetes is a chronic disease with diverse pathologicmanifestations and is accompanied by lipidmetabolism disorders andcirculatory disorders as well as glycometabolism disorders. As theresults, diabetes tends to progress entailing various complications inmany cases. Therefore, it is necessary to select the drug of choice forthe prevailing disease state in each individual case. However, thisselection is often difficult in clinical settings because single use ofeach individual drug can not bring sufficient effects in some diseasestates and there are various problems such as side effect which iscaused by an increased dose or a long-term administration.

SUMMARY OF THE INVENTION

[0007] In view of the above state of the art, the inventors of thepresent invention did much research to develop antidiabetics which wouldnot virtually cause adverse reactions even on long-term administrationand could be effective for a large cohort of the diabetic population. Asa consequence, they discovered that the above object can be accomplishedby using an insulin sensitivity enhancer, such as the drug describedabove, in combination with other antidiabetics differing from saidenhancer in the mechanism of action, and accordingly have perfected thepresent invention.

[0008] The present invention, therefore, relates to:

[0009] 1) Pharmaceutical composition which comprises an insulinsensitivity enhancer in combination with at least one member of thegroup consisting of an α-glucosidase inhibitor, an aldose reductaseinhibitor, a biguanide, a statin compound, a squalene synthesisinhibitor, a fibrate compound, a LDL catabolism enhancer and anangiotensin converting enzyme inhibitor;

[0010] 2) Pharmaceutical composition according to 1), wherein theinsulin sensitivity enhancer is a compound represented by the formula:

[0011] wherein R represents an optionally substituted hydrocarbon orheterocyclic group; Y represents a group represented by —CO—, —CH(OH)—or —NR³— (wherein R³ represents an optionally substituted alkyl group);m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bondor a C₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atomor sulfur atom; R¹ represents hydrogen atom or an alkyl group; ring Emay optionally have 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring, L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; or a pharmacologically acceptable salt thereof;

[0012] 3) Pharmaceutical composition according to 2), wherein thecompound represented by the formula (I) is pioglitazone;

[0013] 4) Pharmaceutical composition according to 1), which comprises aninsulin sensitivity enhancer in combination with an α-glucosidaseinhibitor;

[0014] 5) Pharmaceutical composition according to 4), wherein theα-glucosidase inhibitor is voglibose;

[0015] 6) Pharmaceutical composition according to 4), wherein theinsulin sensitivity enhancer is pioglitazone and the α-glucosidaseinhibitor is voglibose;

[0016] 7) Pharmaceutical composition according to 1), which is forprophylaxis or treatment of diabetes;

[0017] 8) Pharmaceutical composition which comprises a compoundrepresented by the formula:

[0018] wherein R′ represents an optionally substituted hydrocarbon orheterocyclic group; Y represents a group represented by —CO—, —CH(OH)—or —NR³— (wherein R³ represents an optionally substituted alkyl group);m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bondor a C₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atomor sulfur atom; R¹ represents hydrogen atom or an alkyl group; ring Emay optionally have 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; with a proviso that R′ does not representbenzopyranyl group when m and n are O, X represents CH, A represents abond, Q represents sulfur atom, R¹, L and W represent hydrogen atom andring E does not have further substituents; or a pharmacologicallyacceptable salt thereof in combination with an insulin secretionenhancer and/or an insulin preparation;

[0019] 9) Pharmaceutical composition according to 8), wherein thecompound represented by the formula (II) is the compound represented bythe formula:

[0020] 10) Pharmaceutical composition according to 8), wherein thecompound represented by the formula (II) is pioglitazone;

[0021] 11) Pharmaceutical composition according to 8), wherein theinsulin secretion enhancer is glibenclamide;

[0022] 12) Pharmaceutical composition according to 8), wherein thecompound represented by the formula (II) is pioglitazone and the insulinsecretion enhancer is glibenclamide;

[0023] 13) Pharmaceutical composition according to 8), which is forprophylaxis or treatment of diabetes.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The term “insulin sensitivity enhancer” as used in thisspecification means any and all drug substances that restore theimpaired insulin receptor function to deblock insulin resistance andconsequently enhance insulin sensitivity. As examples of the insulinsensitivity enhancer, the compound represented by the formula (I) or apharmacologically acceptable salt thereof can be mentioned.

[0025] In the formula (I), as the hydrocarbon group in the optionallysubstituted hydrocarbon group represented by R, mention is made ofaliphatic hydrocarbon groups, alicyclic hydrocarbon groups,alicyclic-aliphatic hydrocarbon groups, aromatic aliphatic hydrocarbongroups and aromatic hydrocarbon groups. Number of carbon atoms in thesehydrocarbon groups is preferably 1 to 14.

[0026] The aliphatic hydrocarbon groups are preferably those having 1 to8 carbon atoms. As the aliphatic hydrocarbon groups, mention is made ofC₁₋₈ saturated aliphatic hydrocarbon groups (e.g. alkyl group) asexemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl,isohexyl, heptyl and octyl, and C₂₋₈ unsaturated aliphatic hydrocarbongroups (e.g. alkenyl group, alkadienyl group, alkynyl group, alkadiynylgroup) as exemplified by vinyl, 1-propenyl, 2-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl,2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl,1-heptynyl and 1-octynyl.

[0027] The alicyclic hydrocarbon groups are preferably those having 3 to7 carbon atoms. As the alicyclic hydrocarbon groups, mention is made ofC₃₋₇ saturated alicyclic hydrocarbon groups (e.g. cycloalkyl group) asexemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl, and C₅₋₇ unsaturated alicyclic hydrocarbon groups (e.g.cycloalkenyl group, cycloalkadienyl group) as exemplified by1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl,2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl,3-cycloheptenyl and 2,4-cycloheptadienyl.

[0028] As the alicyclic-aliphatic hydrocarbon groups, mention is madeof, among those formed by combination of the above-mentioned alicyclichydrocarbon groups with aliphatic hydrocarbon groups (e.g.cycloalkyl-alkyl group, cycloalkenyl-alkyl group), ones having 4 to 9carbon atoms as exemplified by cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl,3-cyclopentenylmethyl, cyclolhexylmethyl, 2-cyclohexenylmethyl,3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl,cycloheptylmethyl and cycloheptylethyl.

[0029] The aromatic aliphatic hydrocarbon groups are preferably thosehaving 7 to 13 carbon atoms (e.g. aralkyl group). As the aromaticaliphatic hydrocarbon groups, mention is made of C₇₋₉ phenylalkyl asexemplified by benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl,2-phenylpropyl and 1-phenylpropyl, and C₁₁₋₁₃ naphthylalkyl asexemplified by α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl andβ-naphthylethyl.

[0030] As the aromatic hydrocarbon groups, mention is made of, oneshaving 6 to 14 carbon atoms as exemplified by phenyl, naphthyl(α-naphthyl, β-naphthyl).

[0031] In the formula (I), as the heterocyclic group in the optionallysubstituted heterocyclic group represented by R, mention is made of, forexample, 5- to 7-membered heterocyclic groups containing, as a ringcomponent atom, 1 to 4 hetero atoms selected from oxygen atom, sulfuratom and nitrogen atom, and a condensed ring group. As the condensedring, mention is made of, for example, these 5- to 7-memberedheterocyclic groups condensed with 6-membered ring containing one or twonitrogen atoms, benzene ring or 5-membered ring containing one sulfuratom.

[0032] Examples of these heterocyclic groups include 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl,3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl,4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, tetrazol-5-yl,benzimidazol-2-yl, indol-3-yl, 1H-indazol-3-yl,1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyridin-6-yl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,1H-imidazo[4,5-b]pyrazin-2-yl and benzopyranyl. Among them, pyridyl,oxazolyl or thiazolyl group is preferable.

[0033] In the formula (I), the hydrocarbon group and heterocyclic grouprepresented by R may optionally have 1 to 5, preferably 1 to 3substituents at any substitutable positions. Examples of suchsubstituents include aliphatic hydrocarbon group, alicyclic hydrocarbongroup, aryl group, aromatic heterocyclic group, non-aromaticheterocyclic group, halogen atom, nitro group, optionally substitutedamino group, optionally substituted acyl group, optionally substitutedhydroxyl group, optionally substituted thiol group, optionallyesterified carboxyl group, amidino group, carbamoyl group, sulfamoylgroup, sulfo group, cyano group, azido group and nitroso group.

[0034] Examples of the aliphatic hydrocarbon groups include C₁₋₁₅straight-chain or branched aliphatic hydrocarbon groups as exemplifiedby alkyl group, alkenyl group, and alkynyl group.

[0035] Preferable examples of the alkyl group include C₁₋₁₀ alkyl groupssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl,t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl.

[0036] Preferable examples of the alkenyl group include C₂₋₁₀ alkenylgroups such as vinyl, allyl, isopropenyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and5-hexenyl.

[0037] Preferable examples of the alkynyl group include C₂₋₁₀ alkynylgroups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

[0038] As the alicyclic hydrocarbon group, mention is made of C₃₋₁₂saturated or unsaturated alicyclic hydrocarbon groups as exemplified bycycloalkyl group, cycloalkenyl group and cycloalkadienyl group.

[0039] Preferable examples of cycloalkyl group include C₃₋₁₀ cycloalkylgroups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl,bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl.

[0040] Preferable examples of the cycloalkenyl group include C₃₋₁₀cycloalkenyl groups such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl and 3-cyclohexen-1-yl.

[0041] Preferable examples of the cycloalkadienyl group include C₄₋₁₀cycloalkadienyl groups such as 2,4-cyclopentadien-1-yl,2,4-cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl.

[0042] Preferable examples of the aryl group include C₆₋₁₄ aryl groupsSuch as phenyl, naphthyl (1-naphthyl, 2-naphthyl), anthryl, phenanthryland acenaphthylenyl.

[0043] Preferable examples of the aromatic heterocyclic group includearomatic monocyclic heterocyclic groups such as furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl and triazinyl; and aromatic condensedheterocyclic groups such as benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl,indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and1,2,4-triazolo[4,3-b]pyridazinyl.

[0044] Preferable examples of the non-aromatic heterocyclic groupinclude oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl, pyrrolidino, piperidino, morpliolino andthiomorpholino.

[0045] Examples of the halogen atom include fluorine, chlorine, bromineand iodine.

[0046] As the substituted amino group in the optionally substitutedamino group, mention is made of, N-monosubstituted amino group andN,N-disubstituted amino group. Examples of the substituted amino groupsinclude amino groups having once or two substituents selected from C₁₋₁₀alkyl group, C₂₋₁₀ alkenyl group, C₂₋₁₀ alkynyl group, aromatic group,heterocyclic group and C₁₋₁₀ acyl group (e.g. methylamino,dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino,cyclohexylamino, phenylamino, N-methyl-N-phenyl-amino, acetylamino,propionylamino, benzoylamino and nicotinoylamino)

[0047] As the acyl group, mention is made of C₁₋₁₃ acyl groups such asC₁₋₁₀ alkanoyl group, C₃₋₁₀ alkenoyl group, C₄₋₁₀ cycloalkanoyl group,C₄₋₁₀ cycloalkenoyl group and C₆₋₁₂ aromatic carbonyl group.

[0048] Preferable examples of the C₁₋₁₀ alkanoyl group include formylacetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, heptanoyl and octanoyl. Preferable examples of the C₃₋₁₀alkenoyl group include acryloyl, methacryloyl, crotonoyl andisocrotonoyl. Preferable examples of C₄₋₁₀ cycloalkanoyl group includecyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl andcycloheptanecarbonyl. Preferable examples of C₄₋₁₀ cycloalkenoyl groupinclude 2-cyclohexenecarbonyl. Preferable examples of C₆₋₁₂ aromaticcarbonyl group include benzoyl, naphthoyl and nicotinoyl.

[0049] As the substituent in the substituted acyl group, mention is madeof, for example, C₁₋₃ alkyl group, C₁₋₃alkoxy group, halogen atom (e.g.chlorine, fluorine, bromine, etc.), nitro group, hydroxyl group andamino group.

[0050] As the substituted hydroxyl group in the optionally substitutedhydroxyl group, mention is made of, for example, alkoxy group,cycloalkyloxy group, alkenyloxy group, cycloalkenyloxy group, aralkyloxygroup, acyloxy group and aryloxy group.

[0051] Preferable examples of the alkoxy group include C₁₋₁₀ alkoxygroups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy,heptyloxy and nonyloxy. Preferable examples of the cycloalkyloxy groupinclude C₃₋₁₀ cycloalkyloxy groups such as cyclobutoxy, cyclopentyloxyand cyclohexyloxy. Preferable examples of the alkenyloxy group includeC₂₋₁₀ alkenyloxy groups such as allyloxy, crotyloxy, 2-pentenyloxy and3-hexenyloxy. Preferable examples of the cycloalkenyloxy group includeC₃₋₁₀ cycloalkenyloxy groups such as 2-cyclopentenyloxy and2-cyclohexenyloxy. Preferable examples of the aralkyloxy group includeC₇₋₁₀ aryloxy groups such as phenyl-C₁₋₄alkyloxy (e.g. benzyloxy andphenethyloxy). Preferable examples of the acyloxy group include C₂₋₁₃acyloxy group, more preferably C₂₋₄ alkanoyloxy groups (e.g. acetyloxy,propionyloxy, butyryloxy and isobutyryloxy). Preferable examples of thearyloxy group include C₆₋₁₄ aryloxy groups such as phenoxy andnaphthyloxy. The aryloxy group may optionally have one or twosubstituents such as halogen atom (e.g. chlorine, fluorine, bromine).Examples of the substituted aryloxy group include 4-chlorophenoxy.

[0052] As the substituted thiol group in the optionally substitutedthiol group, mention is made of, alkylthio group, cycloalkylthio group,alkenylthio group, cycloalkenylthio group, aralkylthio group, acylthiogroup and arylthio group.

[0053] Preferable examples of the alkylthio group include C₁₋₁₀alkylthio groups such as methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec.-butylthio, t.-butylthio,pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio andnonylthio. Preferable examples of the cycloalkylthio group include C₃₋₁₀cycloalkylthio groups such as cyclobutylthio, cyclopentylthio andcyclohexylthio. Preferable examples of the alkenylthio group includeC₂₋₁₀ alkenylthio groups such as allylthio, crotylthio, 2-pentenylthioand 3-hexenylthio. Preferable examples of the cycloalkenylthio groupinclude C₃₋₁₀ cycloalkenylthio groups such as 2-cyclopentenylthio and2-cyclohexenylthio. Preferable examples of the aralkylthio include C₇₋₁₀aralkylthio groups such as phenyl-C₁₋₄alkylthio (e.g. benzylthio andphenethylthio). Preferable examples of the acylthio group include C₂₋₁₃acylthio group, more preferably C₂₋₄ alkanoylthio groups (e.g.acetylthio, propionylthio, butyrylthio and isobutyrylthio).

[0054] Preferable examples of the arylthio group include C₆₋₁₄ arylthiogroups such as phenylthio and naphthylthio. The arylthio group mayoptionally have one or two substituents such as halogen atom (e.g.chlorine, fluorine, bromine). Examples of the substituted arylthio groupinclude 4-chlorophenylthio.

[0055] As the optionally esterified carboxyl group, mention is made of,for example, alkoxycarbonyl group, aralkyloxycarbonyl group andaryloxycarbonyl group.

[0056] Preferable examples of the alkoxycarbonyl group include C₂₋₅alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and butoxycarbonyl. Preferable examples of thearalkyloxycarbonyl group include C₈₋₁₀ aralkyloxycarbonyl groups such asbenzyloxycarbonyl. Preferable examples of the aryloxycarbonyl groupinclude C₇₋₁₅ aryloxycarbonyl groups such as phenoxycarbonyl andp-tolyloxycarbonyl.

[0057] Among the substituents on the hydrocarbon group and heterocyclicgroup represented by R, C₁₋₁₀ alkyl groups, aromatic heterocyclic groupsand C₆₋₁₄ aryl groups are preferable, and C₁₋₃ alkyl, furyl, thienyl,phenyl and naphthyl are especially preferable.

[0058] In the formula (I), substituents on the hydrocarbon group andheterocyclic group which are represented by R, may, when they arealicyclic hydrocarbon group, aryl group, aromatic heterocyclic group ornon-aromatic heterocyclic group, have one or more, preferably 1 to 3, ofsuitable substituents respectively. Examples of these substituentsinclude C₁₋₆ alkyl groups, C₂₋₆ alkenyl groups, C₂₋₆ alkynyl groups,C₃₋₇ cycloalkyl groups, C₆₋₁₄ aryl groups, aromatic heterocyclic groups(e.g. thienyl, furyl, pyridyl, oxazolyl and thiazolyl), non-aromaticheterocyclic groups (e.g. tetrahydrofuryl, morpholino, thiomorpholino,piperidino, pyrrolidino and piperazino), C₇₋₉ aralkyl groups, aminogroup, N-mono-C₁₋₄ alkylamino groups, N,N-di-C₁₋₄ alkylamino groups,C₂₋₈ acylamino groups (e.g. acetylamino, propionylamino andbenzoylamino), amidino group, C₂₋₈ acyl group (e.g. C₂₋₈ alkanoylgroups), carbamoyl group, N-mono-C₁₋₄ alkyl carbamoyl groups,N,N-di-C₁₋₄ alkyl carbamoyl groups, sulfamoyl group, N-mono-C₁₋₄ alkylsulfamoyl groups, N,N-di-C₁₋₄ alkyl sulfamoyl groups, carboxyl group,C₂₋₈ alkoxycarbonyl groups, hydroxyl group, C₁₋₄ alkoxy groups, C₂₋₅alkenyloxy groups, C₃₋₇ cycloalkyloxy groups, C₇₋₉ aralkyloxy groups,C₆₋₁₄ aryloxy groups, mercapto group, C₁₋₄ alkylthio groups, C₇₋₉aralkylthio groups C₆₋₁₄ arylthio groups, sulfo group, cyano group,azido group, nitro group, nitroso group and halogen atom.

[0059] In the formula (I), R is preferably an optionally substitutedheterocyclic group. R is more preferably pyridyl, oxazolyl or thiazolylgroup which is optionally substituted by 1 to 3 substituents selectedfrom C₁₋₃ alkyl group, furyl group, thienyl group, phenyl group andnaphthyl group.

[0060] R′ in the formula (II) has the same definition as R except thatR′ does not represent benzopyranyl group when m and n are O; Xrepresents CH; A represents a bond; Q represents sulfur atom; R¹, L andM represent hydrogen atom; and ring E does not have furthersubstituents.

[0061] In the formulae (I) and (II), Y represents —CO—, —CH(OH)— or —NR—(wherein R³ represents an optionally substituted alkyl group),preferably —CH(OH)— or —NR³—. As the alkyl group in the optionallysubstituted alkyl group represented by R³, mention is made of, forexample, C₁₋₄ alkyl groups such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec.-butyl and t.-butyl. Examples of the substituentsinclude halogen (e.g., fluorine, chlorine, bromine and iodine), C₁₋₄alkoxy groups (e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy,sec.-butoxy and t.-butoxy), hydroxyl group, nitro group and C₁₋₄ acylgroups (e.g. formyl, acetyl and propionyl).

[0062] The symbol m is 0 or 1, preferably 0.

[0063] The symbol n is 0, 1 or 2, preferably 0 or 1.

[0064] X represents CH or N, preferably CH.

[0065] In the formulae (I) and (II), A represents a bond or a C₁₋₇divalent aliphatic hydrocarbon group. The aliphatic hydrocarbon groupmay be straight-chain or branched, and saturated or unsaturated.Specific examples of the aliphatic hydrocarbon group include saturatedones [e.g. —CH₂—, —CH(CH₃)—, —(CH₂)₂—, —CH(C₂H₅)—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆— and —(CH₂)₇—] and unsaturated ones [e.g. —CH═CH—,—C(CH₃)═CH—, —CH═CH—CH₂—, —C(C₂H₅)═CH—, —CH₂—CH═CH—CH₂—,—CH₂—CH₂—CH═CH—CH₂—. —CH═CH—CH═CH—CH₂— and —CH═CH—CH═CH—CH═CH—CH₂—. A ispreferably a bond or C₁₋₄ divalent aliphatic hydrocarbon groups, thealiphatic hydrocarbon groups preferably being saturated. A is morepreferably a bond or —(CH₂)₂—.

[0066] As the alkyl group represented by R¹, substantially the same oneas the alkyl group in the above-mentioned R³. R¹ is preferably hydrogenatom.

[0067] In the formulae (I) and (II), the partial formula:

[0068] Ring E has 1 to 4 substituents at any substitutable positions.Examples of such substituents include alkyl group, optionallysubstituted hydroxyl group, halogen atom, optionally substituted acylgroup and optionally substituted amino group. These substituents havesubstantially the same meaning as those described as substituents of thehydrocarbon group and heterocyclic group represented by R.

[0069] Ring E, namely the partial formula:

[0070] wherein R² represents hydrogen atom, an alkyl group, anoptionally substituted hydroxyl group, a halogen atom, an optionallysubstituted acyl group, nitro group or an optionally substituted aminogroup.

[0071] As the alkyl group, optionally substituted hydroxyl group,halogen atom, optionally substituted acyl group and optionallysubstituted amino group represented by R², mention is made of thosedescribed as substituents of the hydrocarbon group and heterocyclicgroup represented by R. R² is preferably hydrogen atom, optionallysubstituted hydroxyl group or halogen atom, more preferably hydrogenatom or optionally substituted hydroxyl group, especially preferablyhydrogen atom or C₁₋₄ alkoxy groups.

[0072] In the formulae (I) and (II), L and M represent hydrogen atom, orthey may optionally be combined with each other to form a bond. L and Mare preferably hydrogen atom.

[0073] In the compounds wherein L and M are combined with each other toform a bond, there exist (E)- and (Z)-isomers relative to the doublebond at the 5-position of the azolidinedione ring.

[0074] And, in the compounds wherein L and M respectively representhydrogen atom, there exist (R)- and (S)-optical isomers due to theasymmetric carbon at the 5-position of the azolidinedione ring. Thecompounds include these (R)- and (S)-optical isomers and racemicisomers.

[0075] Preferable examples of the compounds represented by the formula(I) or (II) includes those in which R is pyridyl, oxazolyl or thiazolylgroup optionally having 1 to 3 substituents selected from C₁₋₃ alkyl,furyl, thienyl, phenyl and naphthyl; m is 0; n is 0 or 1; X is CH; A isa bond or —(CH₂)₂—; R¹ is hydrogen atom; ring E, namely the partialformula:

[0076] and R² is hydrogen atom or C₁₋₄ alkoxy group; and L and M areboth hydrogen atom.

[0077] Preferable examples of the compound represented by the formula(I) include

[0078] (1) the compound represented by the formula (III) such as5-[4-[2-(3-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione;5-[4-[2-(4-ethyl-2-pyridyl)ethoxy]-benzyl]-2,4-thiazolidinedione;5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (genericname: pioglitazone); and5-[4-[2-(6-ethyl-2-pyridyl)-ethoxy]benzyl]-2,4-thiazolidinedione;

[0079] (2)(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione;and

[0080] (3)5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(generic name: troglitazone/CS-045).

[0081] The compound represented by the formula (I) is especiallypreferably pioglitazone.

[0082] The compound represented by the formula (II) is preferably thecompound represented by the formula (III) and(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione,more preferably pioglitazone.

[0083] The pharmacologically acceptable salt of the compound representedby the formula (I) or (II) are exemplified by salts with inorganicbases, salts with organic bases, salts with inorganic acids, salts withorganic acids, and salts with basic or acidic amino acids.

[0084] Preferable examples of salts with inorganic bases include saltswith alkali metals such as sodium, potassium, etc., salts with alkalineearth metals such as calcium, magnesium, etc., and salts with aluminum,ammonium, etc.

[0085] Preferable examples of salts with organic bases include saltswith trimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine, etc.

[0086] Preferable examples of salts with inorganic acids include saltswith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc.

[0087] Preferable examples of salts with organic acids include saltswith formic acid, acetic acid, trifluoroacetic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, etc.

[0088] Preferable examples of salts with basic amino acids include saltswith arginine, lysine, ornithine, etc., and preferable examples of saltswith acidic amino acids include salts with aspartic acid, glutamic acid,etc.

[0089] The pharmacologically acceptable salt of the compound representedby the formula (III) is preferably a salt with an inorganic acid, morepreferably a salt with hydrochloric acid. Especially, pioglitazone ispreferably used in the form of salt with hydrochloric acid.

[0090] The compounds represented by the formula (I) or (II) or a saltthereof can be produced in accordance with, for example, methodsdescribed in JPA S55(1980)-22636(EP-A 8203), JPA S60(1985)-208980(EP-A155845), JPA S61(1986)-286376(EP-A 208420), JPA S61(1986)-85372(EP-A177353), JPA S61(1986)-267580(EP-A 193256), JPA H5(1993)-86057(WO92/18501), JPA H7(1995)-82269(EP-A 605228), JPA H7(1995)-101945(EP-A612743), EP-A. 643050, EP-A 710659, etc. or methods analogous thereto.

[0091] Insulin sensitivity enhancers include5-[[3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl]methyl]-2,4-thiazolidinedione(generic name: englitazone) or its sodium salt;

[0092]5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl]phenyl]methyl]-2,4-thiazolidinedione(generic name: darglitazone/CP-86325) or its sodium salt;

[0093]5-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-ylmethyl]-2,4-oxazolidinedione(CP-92768);

[0094] 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31637);

[0095] 4-[(2-naphthalenyl)methyl]-3H-1,2,3,5-oxathiadiazol-2-oxide(AY-30711); and

[0096]5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]-methyl]2,4-thiazolinedione(BRL-49653), etc. in addition to compounds mentioned hereinbefore.

[0097] In the present invention, examples of the drug which is used incombination with the above-mentioned insulin sensitivity enhancerinclude an α-glucosidase inhibitor, an aldose reductase inhibitor, abiguanide, a statin compound, a squalene synthesis inhibitor, a fibratecompound, a LDL catabolism enhancer and an angiotensin converting enzymeinhibitor.

[0098] α-Glucosidase inhibitors are drugs which inhibit digestiveenzymes such as amylase, maltase, α-dextrinase, sucrase, etc. to retarddigestion of starch and sugars. Examples of the α-glucosidase inhibitorsinclude acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (generic name;voglibose), miglitol, etc. with preferance given to voglibose.

[0099] Aldose reductase inhibitors are drugs which inhibit thefirst-stage rate-limiting enzyme in the polyol pathway to prevent orarrest diabetic complications. In the hyperglycemic state of diabetes,the utilization of glucose in the polyol pathway is increased and theexcess sorbitol accumulated intracellularly as a consequence acts as atissue toxin and hence evokes the onset of complications such asdiabetic neuropathy, retinopathy, and nephropathy. Examples of thealdose reductase inhibitors include tolurestat; epalrestat;3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid;2,7-difluoro-spiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione (genericname: imirestat);

[0100]3-[(4-bromo-2-fluorophenyl)methyl]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid (generic name: zenarestat);

[0101]6-fluoro-2,3-dihydro-2′,5′-dioxo-spiro[4H-1-benzopyran-4,4′-imidazolidine]-2-carboxamide(SNK-860);

[0102] zopolrestat; sorbinil; and

[0103] 1-[(3-bromo-2-benzofuranyl)sulfonyl]-2,4-imidazolidinedione(M-16209), etc.

[0104] Biguanides are drugs having actions of stimulation of anaerobicglycolysis, increase of the sensitivity to insulin in the peripheraltissues, inhibition of glucose absorption from the intestine,suppression of hepatic gluconeogenesis, and inhibition of fatty acidoxidation. Examples of the biguanides include phenformin, metformin,buformin etc.

[0105] Statin compounds are drugs having actions of lowering-bloodcholesterol levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA)reductase. Examples of the statin compounds include pravastatin and itssodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, etc.

[0106] Squalene synthesis inhibitors are drugs having actions oflowering blood cholesterol levels by inhibiting synthesis of squalene.Examples of the squalene synthesis inhibitors include(S)-α-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonicacid, mono potassium salt (BMS-188494).

[0107] Fibrate compounds are drugs having actions of lowering bloodcholesterol levels by inhibiting synthesis and secretion oftriglycerides in liver and activating a lipoprotein lipase.

[0108] Examples of the fibrate compounds include bezafibrate,beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate,clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, theofibrate, etc.

[0109] LDL catabolism enhancers are drugs having actions of loweringblood cholesterol levels by increasing the number of LDL (low-densitylipoprotein) receptors.

[0110] Examples of the LDL catabolism enhancers include the compoundwhich is described in JPA H7(1995)-316144 and represented by theformula:

[0111] wherein R⁴, R⁵, R⁶ and R⁷ are the same or different, andrepresent hydrogen atom, a halogen atom, a lower alkyl group or a loweralkoxy group; r is 0-2; s is 2-4; p is 1-2; or a salt thereof;specificallyN-[2-[4-bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl]-7,7-diphenyl-2,4,6-heptatrienicacid amide, etc.

[0112] The above-mentioned statin compounds, squalene synthesisinhibitors, fibrate compounds and LDL, catabolism enhancers can besubstituted with other drugs having the property to lower bloodcholesterol and triglyceride levels. Examples of these drugs includenicotinic acid derivatives such as nicomol and niceritrol; antioxidantssuch as probucol; and ion-exchange resins such as colestyramin.

[0113] Angiotensin converting enzyme inhibitors are drugs having actionsof partially lowering blood glucose levels as well as lowering bloodpressure by inhibiting angiotensin converting enzymes. Examples of theangiotensin converting enzyme inhibitors include captopril, enalapril,alacepril, delapril, ramipril, lisinopril, imidapril, benazepril,ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril,perindopril, quinapril, spirapril, temocapril, trandolapril, etc.

[0114] In the present invention, especially preferred is thepharmaceutical composition which comprises an insulin sensitivityenhancer in combination with an α-glucosidase inhibitor. The insulinsensitivity enhancer is especially preferably pioglitazone, and theα-glucosidase inhibitor is especially preferably voglibose.

[0115] In the present invention, examples of the drug which is used incombination with the compound represented by the formula (II) or apharmacologically acceptable salt thereof include an insulin secretionenhancer and/or an insulin preparation.

[0116] Insulin secretion enhancers are drugs having the property topromote secretion of insulin from pancreatic β cells. Examples of theinsulin secretion enhancers include sulfonylureas (SU). Thesulfonylureas (SU) are drugs which promote secretion of insulin frompancreatic β cells by transmitting signals of insulin secretion via SUreceptors in the cell membranes. Examples of the SU include tolbutamide;chlorpropamide; tolazamide; acetohexamide;4-chloro-N-[(1-pyrolidinylamino)carbonyl]-benzenesulfonamide (genericname: glycopyramide) or its ammonium salt; glibenclamide (glyburide);gliclazide; 1-butyl-3-metanilylurea; carbutamide; glibonuride;glipizide; gliquidone; glisoxepid; glybuthiazole; glibuzole;glyhexamide; glymidine; glypinamide; phenbutamide; tolcyclamide, etc.

[0117] Insulin secretion enhancers includeN-[[4-(1-methlylethyl)cyclohexyl)carbonyl]-D-phenylalanine (AY-4166);calcium (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionatedihydrate (KAD-1229); and glimepiride (Hoe 490), etc. in addition tocompounds mentioned hereinbefore. The insulin secretion enhancer isespecially preferably glibenclamide.

[0118] Examples of the insulin preparations include animal insulinpreparations typically extracted from bovine or porcine pancreas andhuman insulin preparations synthesized by genetic engineering techniquestypically using Escherichia coli or yeasts. While insulin preparationsare available in a variety of types, e.g. immediate-acting,bimodal-acting, intermediate-acting, and long-acting, these types ofpreparations can be selectively administered according to the patient'scondition.

[0119] In the present invention, especially preferred is thepharmaceutical composition which comprises the compound represented bythe formula (II) or a pharmacologically acceptable salt thereof incombination with an insulin secretion enhancer. The compound representedby the formula (II) or a pharmacologically acceptable salt thereof isespecially preferably pioglitazone, and the insulin secretion enhanceris especially preferably glibenclamide.

[0120] The pharmaceutical composition comprising an insulin sensitivityenhancer in combination with at least one member selected from the groupconsisting of an α-glucosidase inhibitor, an aldose reductase inhibitor,a biguanide, a statin compound, a squalene synthesis inhibitor, afibrate compound, a LDL catabolism enhancer and an angiotensinconverting enzyme inhibitor; and the pharmaceutical compositioncomprising the compound represented by the formula (II) or apharmacologically acceptable salt thereof in combination with an insulinsecretion enhancer and/or an insulin preparation, both provided inaccordance with the present invention, can be respectively put to use bymixing the respective active components either all together orindependently with a physiologically acceptable carrier, excipient,binder, diluent, etc. and administering the mixture or mixtures eitherorally or non-orally as a pharmaceutical composition. When the activecomponents are formulated independently, the respective formulations canbe extemporaneously admixed using a diluent or the like and administeredor can be administered independently of each other, either concurrentlyor at staggered times to the same subject.

[0121] The dosage form for said pharmaceutical composition includes suchoral dosage forms as granules, powders, tablets, capsules, syrups,emulsions, suspensions, etc. and such non-oral dosage forms asinjections (e.g. subcutaneous, intravenous, intramuscular andintraperitoneal injections), drip infusions, external application forms(e.g. nasal spray preparations, transdermal preparations, ointments,etc.), and suppositories (e.g. rectal and vaginal suppositories).

[0122] These dosage forms can be manufactured by the per se knowntechnique conventionally used in pharmaceutical procedures. The specificmanufacturing procedures are as follows.

[0123] To manufacture an oral dosage form, an excipient (e.g. lactose,sucrose, starch, mannitol, etc.), a disintegrator (e.g. calciumcarbonate, carboxymethylcellulose calcium, etc.), a binder (e.g.α-starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose, etc.), and a lubricant (e.g. talc, magnesiumstearate, polyethylene glycol 6000, etc.), for instance, are added tothe active component or components and the resulting composition iscompressed. Where necessary, the compressed product is coated, by theper se known technique, for masking the taste or for enderic dissolutionor sustained release. The coating material that can be used includes,for instance, ethylcellulose, hydroxymethylcellulose; polyoxyethyleneglycol, cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, and Eudragit (Rohm & Haas, Germany, methacrylic-acryliccopolymer).

[0124] Injections can be manufactured typically by the followingprocedure. The active component or components are dissolved, suspendedor emulsified in an aqueous vehicle (e.g. distilled water, physiologicalsaline, Ringer's solution, etc.) or an oily vehicle (e.g. vegitable oilsuch as olive oil, sesame oil, cottonseed oil, corn oil, etc. orpropylene glycol) together with a dispersant (e.g. Tween 80 (AtlasPowder, U.S.A.), HCO 60 (Nikko Chemicals), polyethylene glycol,carboxymethylcellulose, sodium alginate, etc.), a preservative. (e.g.methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol,chlorobutanol, phenol, etc.), an isotonizing agent (e.g. sodiumchloride, glycerol, sorbitol, glucose, inverted sugar, etc.) and otheradditives. If desired, a solubilizer (e.g. sodium salicylate, sodiumacetate, etc.), a stabilizer (e.g. human serum albumin), a soothingagent (e.g. benzalkonium chloride, procaine hydrochloride, etc.) andother additives can also be added.

[0125] A dosage form for external application can be manufactured byprocessing the active component or components into a solid, semi-solidor liquid composition. To manufacture a solid composition, for instance,the active component or components, either as they are or in admixturewith an excipient (e.g. lactose, mannitol, starch, microcrystallinecellulose, sucrose, etc.), a thickener (e.g. natural gums, cellulosederivatives, acrylic polymers, etc.), etc., are processed into powders.The liquid composition can be manufactured in substantially the samemanner as the injections mentioned above. The semi-solid composition ispreferably provided in a hydrous or oily gel form or an ointment form.These compositions may optionally contain a pH control agent (e.g.carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodiumhydroxide, etc.), and a preservative (e.g. p-hydroxybenzoic acid esters,chlorobutanol, benzalkonium chloride, etc.), among other additives.

[0126] Suppositories can be manufactured by processing the activecomponent or components into an oily or aqueous composition, whethersolid, semi-solid or liquid. The oleaginous base that can be usedincludes, for instance, higher fatty acid glycerides [e.g. cacao butter,Witepsols (Dinamit-Nobel), etc.], medium-chain fatty acids [e.g.Migriols (Dinamit-Nobel), etc.], vegetable oils (e.g. sesame oil,soybean oil, cottonseed oil, etc.), etc. The water-soluble baseincludes, for instance, polyethylene glycols, propylene-glycol, etc. Thehydrophilic base includes, for instance, natural gums, cellulosederivatives, vinyl polymers, and acrylic polymers, etc.

[0127] The pharmaceutical composition of the present invention is low intoxicity and can be safely used in mammals (e.g. humans, mice, rats,rabbits, dogs, cats, bovines, horses, swines, monkeys).

[0128] The dosage of the pharmaceutical composition of the presentinvention may be appropriately determined with reference to the dosagesrecommended for the respective active components and can be selectedappropriately according to the recipient, the recipient's age and bodyweight, current clinical status, administration time, dosage form,method of administration, and combination of the active components,among other factors. For example, the dosage of the insulin sensitivityenhancer for an adult can be selected from the clinical oral dose rangeof 0.01 to 10 mg/kg body weight (preferably 0.05 to 10 mg/kg bodayweight, more preferably 0.05 to 5 mg/kg body weight) or the clinicalparenteral dose range of 0.005 to 10 mg/kg body weight (preferably 0.01to 10 mg/kg body weight, more preferably 0.01 to 1 mg/kg body weight).The other active component or components having different modes ofaction for use in combination can also be used in dose ranges selectedby referring to the respective recommended clinical dose ranges. Thepreferred frequency of administration is 1 to 3 times a day.

[0129] The proportions of the active components in the pharmaceuticalcomposition of the present invention can be appropriately selectedaccording to the recipient, the recipient's age and body weight, currentclinical status, administration time, dosage form, method ofadministration, and combination of active components, among otherfactors. When, for example, the compound represented by the formula (I)or a pharmacologically acceptable salt thereof (e.g. pioglitazone) whichis the insulin sensitivity enhancer and voglibose which is anα-glucosidase inhibitor are to be administered in combination to a humansubject, voglibose is used in a proportion of usually about 0.0001 to0.2 weight parts and preferably about 0.001 to 0.02 weight partsrelative to 1 weight part of the compound or a salt thereof. When, forexample, the compound represented by the formula (II) or apharmacologically acceptable salt thereof and glibenclamide which is aninsulin secretion enhancer are to be administered in combination to ahuman subject, glibenclamide is used in a proportion of usually about0.002 to 5 weight parts and preferably about 0.025 to 0.5 weight parts,relative to 1 weight part of the compound or a pharmacologicallyacceptable salt thereof.

[0130] The pharmaceutical composition of the present invention shows amarked synergistic effect compared with administration of either activecomponent alone. For example, compared with cases in which each of theseactive components was administered to diabetic Wistar fatty rats withgenetical obsesity, administration of these active components incombination resulted in marked improvements in both hyperglycemia andreduced glucose tolerance. Thus, the pharmaceutical composition of thepresent invention lowers blood glucose in diabetics more effectivelythan it is the case with administration of each component drug aloneand, therefore, can be used advantageously for the prophylaxis andtreatment of diabetic complications.

[0131] Furthermore, since the pharmaceutical composition of the presentinvention develops sufficient efficacy with reduced doses as comparedwith the administration of any one of the active components alone, theside effects of the respective components (e.g. gastrointestinaldisorders such as diarrhea, etc.) can be reduced.

[0132] The following working examples and experimental examples aremerely intended to illustrate the present invention in further detailbut should by no means be construed as defining the scope of theinvention.

[0133] The pharmaceutical composition of the present invention can beprepared according to the following formulations.

WORKING EXAMPLE 1

[0134] Capsules (1) Pioglitazone hydrochloride   30 mg (2) Voglibose 0.2 mg (3) Lactose   60 mg (4) Microcrystalline cellulose 79.8 mg (5)Magnesium stearate   10 mg Total  180 mg

[0135] The whole amounts of (1), (2), (3) and (4) and half the amount of(5) are mixed well and granulated in the conventional manner. Then, thebalance of (5) is added and, after mixing, the whole composition isfilled in a gelatin hard capsule shell.

WORKING EXAMPLE 2

[0136] Tablets (1) Pioglitazone hydrochloride   10 mg (2) Glibenclamide 1.25 mg (3) Lactose 86.25 mg (4) Corn starch   20 mg (5) Polyethyleneglycol  2.5 mg (6) Hydroxypropylcellulose    4 mg (7) Carmellose calcium 5.5 mg (8) Magnesium stearate  0.5 mg   130 mg (per tablet)

[0137] The whole amounts of (1), (2), (3), (4), and (5), ⅔ amounts of(6) and (7), and ½ amount of (8) are mixed well and granulated in theconventional manner. Then, the balances of (6), (7) and (8) are added tothe granules, which is mixed well and the whole composition iscompressed with a tablet machine. The adult dosage is 3 tablets/day, tobe taken in 1 to 3 divided doses.

WORKING EXAMPLE 3

[0138] Capsules (1) Pioglitazone hydrochloride  10 mg (2) Epalrestat  50mg (3) Lactose  55 mg (4) Microcrystalline cellulose  55 mg (5)Magnesium stearate  10 mg Total 180 mg

[0139] The whole amounts of (1); (2), (3) and (4) and ½ amount of (5)are mixed well and granulated in the conventional manner. Then, thebalance of (5) is added and the whole composition is filled in gelatincapsule shell. The adult dosage is 3 capsules/day, to be taken in 1 to 3divided doses.

EXPERIMENTAL EXAMPLE 1

[0140] Effect of pioglitazone hydrochloride in combination withα-glucosidase inhibitor in genetically obese and diabetic Wistar fattyrats

[0141] Male Wistar fatty rats aged 14-19 weeks were divided into 4groups of 5-6, and pioglitazone hydrochloride (1 mg/kg body wt./day,p.o.) and/or voglibose (an α-glucosidase inhibitor) (0.31 mg/kg bodywt./day; administered by mixing in commercial diet at a rate of 5 ppm)was administered for 14 days. The blood was then collected from the tailvein and the plasma glucose and hemoglobin A₁ were determined by theenzymatic method (Encore Chemical System, Baker) and using a commercialkit (NC-ROPET, Nippon Chemiphar Co.), respectively. The results wereexpressed in mean ± standard deviation for each group (n=5-6) andanalyzed by Dunnett's test, which are shown in Table 1. The 1% level ofsignificance was used. TABLE 1 Plasma glucose Hemoglobin A₁ Group(mg/dl) (%) Control 345 ± 29  5.7 ± 0.4 Pioglitazone 215 ± 50* 5.2 ± 0.3Voglibose 326 ± 46  6.0 ± 0.6 Pioglitazone + voglibose 114 ± 23*  4.5 ±0.4*

[0142] It is apparent from Table 1 that both the blood glucose andhemoglobin A₁ levels were remarkably lowered by combined administrationof pioglitazone and voglibose as compared with the administration ofeither drug alone.

EXPERIMENTAL EXAMPLE 2

[0143] Effect of pioglitazone hydrochloride in combination with aninsulin secretion enhancer in genetically obese arid diabetic Wistarfatty rats

[0144] Male Wistar fatty rats aged 13-14 weeks were divided into 4groups of 5, and pioglitazone hydrochloride (3 mg/kg/day, p.o.) and/orglibenclamide (an insulin secretion enhancer) (3 mg/kg/day, p.o.) wasadministered for 7 days. Following an overnight fast, the oral glucoseloading test (2 g glucose/kg/5 ml, p.o.) was carried out. Prior toglucose loading and 120 and 240 minutes after the loading, blood wascollected from the tail vein and the plasma glucose was assayed by theenzymatic method (Encore Chemical System, Baker). The results wereexpressed in mean ± SD for each group (n=5) and analyzed by Dunnett'stest, which are shown in Table 2. TABLE 2 Plasma glucose (mg/dl) Group 0min. 120 min. 240 min. Control 119 ± 9  241 ± 58  137 ± 10  Pioglitazone102 ± 12 136 ± 17* 102 ± 9*  Glibenclamide 118 ± 12 222 ± 61  106 ± 24*Pioglitazone + glibenclamide 108 ± 3   86 ± 10* 60 ± 5*

[0145] It is apparent from Table 2 that the increase of blood sugarfollowing glucose loading was remarkably inhibited by the combinedadministration of pioglitazone and glibenclamide as compared with theadministration of either drug alone.

[0146] The pharmaceutical composition of the present invention shows apotent depressive effect on diabetic hyperglycemia and is useful forprophylaxis and treatment of diabetes. Moreover, this pharmaceuticalcomposition is useful for prophylaxis and treatment of diabeticcomplications such as diabetic neuropathy, nephropathy, retinopathy,macroangiopathy, and osteopenia. In addition, by appropriately selectingthe kinds of component drugs, administration route, dosage, etc.according to clinical status, stable hypoglycemic efficacy in long-termtherapy can be expected with an extremely low risk of side effect.

1-51. (Canceled)
 52. A composition for the treatment of diabetescomprising: (a) a therapeutically effective amount of an insulinsensitivity enhancer, and (b) a therapeutically effective amount anantidiabetic, wherein the antidiabetic differs from the insulinsensitivity enhancer in the mechanism of action.
 53. The composition ofclaim 52, wherein the antidiabetic is selected from the group consistingof an insulin preparation, a sulfonylurea, a biguanide, and anα-glucosidase inhibitor.
 54. The composition of claim 53, wherein theantidiabetic is an insulin preparation and wherein the insulinsensitivity enhancer is a compound represented by the formula:

wherein R′ represents an optionally substituted hydrocarbon orheterocycle group; Y represents a group represented by —CO—, —CH(OH)— or—NR³— wherein R³ represents an optionally substituted alkyl group; m is0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or aC₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atom orsulfur atom; R¹ represents hydrogen atom or an alkyl group; ring E mayoptionally have further 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; wherein R′ does not represent benzopyranyl groupwhen m and n are O, X represents CH, A represents a bond, Q representssulfur atom, R¹, L and M represent hydrogen atom, and ring E does nothave further substituents or a pharmacologically acceptable saltthereof.
 55. A composition for the treatment of diabetes in a mammalcomprising: (a) a therapeutically effective amount of an insulinpreparation; and, (b) a therapeutically effective amount of one or moreof an orally administrable insulin sensitivity enhancer, wherein theinsulin sensitivity enhancer enhances insulin sensitivity and reducesthe therapeutically effective amount of insulin preparation per dose ofinsulin preparation.
 56. The composition of claim 55, wherein theinsulin sensitivity enhancer is a compound represented by the formula:

wherein R′ represents an optionally substituted hydrocarbon orheterocycle group; Y represents a group represented by —CO—, —CH(OH)— or—NR³— wherein R³ represents an optionally substituted alkyl group; m is0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or aC₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atom orsulfur atom; R¹ represents hydrogen atom or an alkyl group; ring E mayoptionally have further 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; wherein R′ does not represent benzopyranyl groupwhen m and n are O, X represents CH, A represents a bond, Q representssulfur atom, R¹, L and M represent hydrogen atom, and ring E does nothave further substituents or a pharmacologically acceptable saltthereof.
 57. The composition of claim 55, further comprising aphysiologically acceptable carrier.
 58. The composition of claim 55,wherein the insulin sensitivity enhancer is present in the compositionin the range of about 0.01 to 10 mg/kg of subject body weight.
 59. Thecomposition of claim 52, wherein the insulin sensitivity enhancer isselected from the group consisting of BRL-49653, pioglitazonehydrochloride, and troglitazone.
 60. A method for the treatment ofdiabetes comprising administering to a mammal in need thereof atherapeutically effective amount of an insulin sensitivity enhancer witha therapeutically effective amount of an antidiabetic.
 61. The method ofclaim 60, wherein the antidiabetic is an insulin preparation.
 62. Thecomposition of claim 61, wherein the insulin sensitivity enhancer is acompound represented by the formula:

wherein R′ represents an optionally substituted hydrocarbon orheterocycle group; Y represents a group represented by —CO—, —CH(OH)— or—NR³— wherein R³ represents an optionally substituted alkyl group; m is0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or aC₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atom orsulfur atom; R¹ represents hydrogen atom or an alkyl group; ring E mayoptionally have further 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; wherein R′ does not represent benzopyranyl groupwhen m and n are O, X represents CH, A represents a bond, Q representssulfur atom, R¹, L and M represent hydrogen atom, and ring E does nothave further substituents; or a pharmacologically acceptable saltthereof.
 63. The method of claim 60, wherein a physiologicallyacceptable carrier is administered with the antidiabetic.
 64. A methodas claimed in claim 60, wherein the antidiabetic is selected from thegroup consisting of: (a) an insulin preparation; (b) a sulfonylurea; (c)a biguanide; and (d) an α-glucosidase inhibitor.
 65. A method for thetreatment of diabetes comprising administering to a mammal in needthereof a therapeutically effective amount of an insulin sensitivityenhancer with a therapeutically effective amount of an orallyadministrable antidiabetic, wherein (1) the insulin sensitivity enhanceris selected from the group consisting of BRL-49653, pioglitazonehydrochloride, and troglitazone, and wherein (2) the antidiabetic isselected from the group consisting of an insulin preparation, asulfonylurea, a biguanide, and an α-glucosidase inhibitor.
 66. Themethod of claim 65, wherein the antidiabetic is an orally administrableantidiabetic.
 67. The method of claim 66, wherein the antidiabetic is aninsulin preparation.
 68. The method of claim 67, wherein the insulinsensitivity enhancer is a compound represented by the formula:

wherein R′ represents an optionally substituted hydrocarbon orheterocycle group; Y represents a group represented by —CO—, —CH(OH)— or—NR³— wherein R³ represents an optionally substituted alkyl group; m is0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or aC₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atom orsulfur atom; R¹ represents hydrogen atom or an alkyl group; ring E mayoptionally have further 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; wherein R′ does not represent benzopyranyl groupwhen m and n are O, X represents CH, A represents a bond, Q representssulfur atom, R¹, L and M represent hydrogen atom, and ring E does nothave further substituents or a pharmacologically acceptable saltthereof.
 69. The method of claim 65, wherein the composition isformulated for injection. PAGE
 23. 70. A composition for the treatmentof diabetes comprising: (a) a therapeutically effective amount of aninsulin sensitivity enhancer, and (b) a therapeutically effective amountof an antidiabetic, wherein the antidiabetic is an insulin preparation.71. The composition of claim 70, wherein the insulin sensitivityenhancer is a compound represented by the formula:

wherein R′ represents an optionally substituted hydrocarbon orheterocycle group; Y represents a group represented by —CO—, —CH(OH)— or—NR³— wherein R³ represents an optionally substituted alkyl group; m is0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or aC₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atom orsulfur atom; R¹ represents hydrogen atom or an alkyl group; ring E mayoptionally have further 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; wherein R′ does not represent benzopyranyl groupwhen m and n are O, X represents CH, A represents a bond, Q representssulfur atom, R¹, L and M represent hydrogen atom, and ring E does nothave further substituents or a pharmacologically acceptable saltthereof.
 72. A composition for the treatment of diabetes comprising: (a)a therapeutically effective amount of an insulin sensitivity enhancer,and (b) a therapeutically effective amount of an antidiabetic, whereinthe antidiabetic is a sulfonylurea.
 73. A composition for the treatmentof diabetes comprising: (a) a therapeutically effective amount of aninsulin sensitivity enhancer, and (b) a therapeutically effective amountof an antidiabetic, wherein the antidiabetic is a biguanide.
 74. Acomposition for the treatment of diabetes comprising: (a) atherapeutically effective amount of an insulin sensitivity enhancer,wherein the insulin sensitivity enhancer is BRL-49653, and (b) atherapeutically effective amount of an antidiabetic, wherein theantidiabetic is an insulin preparation.
 75. The composition of claim 74,wherein the insulin sensitivity enhancer is a compound represented bythe formula:

wherein R′ represents an optionally substituted hydrocarbon orheterocycle group; Y represents a group represented by —CO—, —CH(OH)— or—NR³— wherein R³ represents an optionally substituted alkyl group; m is0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or aC₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atom orsulfur atom; R¹ represents hydrogen atom or an alkyl group; ring E mayoptionally have further 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; wherein R′ does not represent benzopyranyl groupwhen m and n are O, X represents CH, A represents a bond, Q representssulfur atom, R¹, L and M represent hydrogen atom, and ring E does nothave further substituents or a pharmacologically acceptable saltthereof.
 76. A composition for the treatment of diabetes comprising: (a)a therapeutically effective amount of an insulin sensitivity enhancer,wherein the insulin sensitivity enhancer is BRL-49653; and (b) atherapeutically effective amount of an antidiabetic, wherein theantidiabetic is a sulfonylurea.
 77. A composition for the treatment ofdiabetes comprising: (a) a therapeutically effective amount of aninsulin sensitivity enhancer, wherein the insulin sensitivity enhanceris BRL-49653, and (b) a therapeutically effective amount of anantidiabetic, wherein the antidiabetic is a biguanide.
 78. A compositionfor the treatment of diabetes comprising: (a) a therapeuticallyeffective amount of an insulin sensitivity enhancer, wherein the insulinsensitivity enhancer is pioglitazone hydrochloride, and (b) atherapeutically effective amount of an antidiabetic, wherein theantidiabetic is an insulin preparation.
 79. The composition of claim 78,wherein the insulin sensitivity enhancer is a compound represented bythe formula:

wherein R′ represents an optionally substituted hydrocarbon orheterocycle group; Y represents a group represented by —CO—, —CH(OH)— or—NR³— wherein R³ represents an optionally substituted alkyl group; m is0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or aC₁₋₇ divalent aliphatic hydrocarbon group; Q represents oxygen atom orsulfur atom; R¹ represents hydrogen atom or an alkyl group; ring E mayoptionally have further 1 to 4 substituents, and the substituents mayoptionally be combined with R¹ to form a ring; L and M respectivelyrepresent hydrogen atom, or L and M may optionally be combined with eachother to form a bond; wherein R′ does not represent benzopyranyl groupwhen m and n are O, X represents CH, A represents a bond, Q representssulfur atom, R¹, L and M represent hydrogen atom, and ring E does nothave further substituents or a pharmacologically acceptable saltthereof.
 80. A composition for the treatment of diabetes comprising: (a)a therapeutically effective amount of an insulin sensitivity enhancer,wherein the insulin sensitivity enhancer is pioglitazone hydrochloride,and (b) a therapeutically effective amount of an antidiabetic, whereinthe antidiabetic is an insulin preparation, and wherein the compositionis formulated for injection.
 81. A composition for the treatment ofdiabetes comprising: (a) a therapeutically effective amount of aninsulin sensitivity enhancer, wherein the insulin sensitivity enhanceris pioglitazone hydrochloride, and (b) a therapeutically effectiveamount of an antidiabetic, wherein the antidiabetic is a sulfonylurea.82. A composition for the treatment of diabetes comprising: (a) atherapeutically effective amount of an insulin sensitivity enhancer,wherein the insulin sensitivity enhancer is pioglitazone hydrochloride,and (b) a therapeutically effective amount of an antidiabetic, whereinthe antidiabetic is a biguanide.
 83. A method for the treatment ofdiabetes comprising administering to a mammal in need thereof atherapeutically effective amount of an insulin sensitivity enhancer witha therapeutically effective amount of an orally administrableantidiabetic, wherein (1) the insulin sensitivity enhancer is BRL-49653,and wherein (2) the antidiabetic is a sulfonylurea.
 84. A method for thetreatment of diabetes comprising administering to a mammal in needthereof a therapeutically effective amount of an insulin sensitivityenhancer with a therapeutically effective amount of an orallyadministrable antidiabetic, wherein (1) the insulin sensitivity enhanceris BRL-49653, and wherein (2) the antidiabetic is a biguanide.
 85. Amethod for the treatment of diabetes comprising administering to amammal in need thereof a therapeutically effective amount of an insulinsensitivity enhancer with a therapeutically effective amount of anorally administrable antidiabetic, wherein (1) the insulin sensitivityenhancer is pioglitazone hydrochloride, and wherein (2) the antidiabeticis a sulfonylurea.
 86. A method for the treatment of diabetes comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of an insulin sensitivity enhancer with a therapeuticallyeffective amount of an orally administrable antidiabetic, wherein (1)the insulin sensitivity enhancer is pioglitazone hydrochloride, andwherein (2) the antidiabetic is a biguanide.